Lab Value Changes in Transgender Females

For our next edition of transgender laboratory medicine, we will explore how transgender women use hormone therapy to physically transition to their affirmed female gender. While transgender men just take testosterone, transgender women take both estradiol and an anti-androgen. In the United States, that anti-androgen is spironolactone.

Figure 1. I was amazed in freshman biology by how structurally similar these hormones were and how they lead to such dramatically different phenotypes. Spironolactone is quite a bit different with the same cholesterol backbone. Credit Wikipedia

Estradiol is administered either as an oral pill, an injectable liquid or a transdermal patch. The estradiol pills are the cheapest option as they have been made generic for use as birth control. The transdermal can be the easiest to use, but is also the most expensive version and may not deliver as much estradiol as the other routes. Oral estradiol usually starts in adults at a low-dose (2 mg) then is titrated up to 4-6 mg and rarely up to 8mg. The end-point of estradiol titration is not to reach a certain hormone level, but to achieve desired physical traits. Endocrine guidelines do suggest keeping estradiol levels below peak physiologic levels (200 pg/mL).1 While little evidence currently exists for side effects of supraphysiologic estradiol, blood clots are a serious known side effect.

Part of the reason for anti-androgens in treating transgender women, is that even in women, testosterone levels are orders of magnitude higher. Spironolactone is primarily used as a glucocorticoid analog to block the mineralocorticoid receptor in the kidney to induce diuresis while retaining potassium. The structure of spironolactone is similar enough totestosterone that it also binds the androgen receptor and blocks the effect of testosterone. While enlarged breasts are considered a side effect in heart failure patients, it is an intended effect of spironolactone in transgender women. While hyperkalemia (high potassium) is a well known adverse effect of spironolactone, it seems to manifest more in patients with co-morbid conditions such as heart or kidney failure rather than in healthy patients.2

Table 1. This table describes the time frame of physical traits that manifest in transgender women while taking feminizing hormone therapy. Based on Hembree et al. 2017 (1).

For feminizing hormone therapy, red blood cell indices are the one of the most responsive laboratory parameters. The hemoglobin, hematocrit, and RBC number are all seen to decrease during hormone therapy in transgender women. A previous study of 55 transgender women3 showed that hemoglobin levels decreased significantly from cis-gender male levels to be not significantly different from cis-gender female hemoglobin. With a larger patient group, we were able to confirm this previous finding of decreased hemoglobin, but transgender women’s hemoglobin levels are still significantly different from individuals with sex-assigned female at birth (Figure 2).

Roberts et al also found that creatinine levels remain closer to cisgender male levels compared to cisgender female creatinine values3. This brought up the concept that not all lab values change predictably to the reference interval of the opposite gender. We further confirmed this finding in our larger cohort, but we further found a significant difference in transgender women from their baseline levels (Figure 3).

Overall, red blood cell and creatinine levels change the most in transgender women taking hormone therapy, but they don’t go as far as being comparable to lab values of individuals of the opposite sex assigned at birth. Our summary of this data will be published soon and interested labs can note what we found to be the central 95th percentile of common lab values including those presented here. I will go into greater detail about some unexpected effects of hormone therapy in following blog posts. I hope you’re looking forward to it as much as I am!

-Jeff SoRelle, MD is a Molecular Genetic Pathology fellow at the University of Texas Southwestern Medical Center in Dallas, TX. His clinical research interests include understanding how the lab intersects with transgender healthcare and advancing quality in molecular diagnostics.